Iodine is a non-metallic element of the halogen family, and is the only halogen that is solid at ordinary temperatures. Iodine has been shown to have a range in valence of from -1 to +7, and compounds thermodynamically stable with respect to their constituent elements are known to exist for all of the oxidation states of iodine.
Iodine was discovered early in the 19th century, and the first practical therapeutic application of iodine was as a remedy for goiter. This use was followed shortly thereafter with use as a germicide for treatment of wounds. It was during the American war between the states that the first wide-spread use of iodine as an antiseptic and germicide was developed for the treatment of battle wounds. Since that time, iodine has been recognized to be a preferred germicide, but because of certain inherent chemical, physical and biological properties, the antiseptic degerming use of iodine for humans and animals has been limited.
Elemental iodine has a high vapor pressure which results in pharmaceutical compositions having varying germicidal potency, since the iodine content volatilizes from an antiseptic preparation upon aging. Moreover, the high vapor pressure of iodine limits its use in closed compartments, such as body cavities or under a bandage, because of the corrosive destruction and irritation of skin, mucous membranes, and other vital tissues by the elemental iodine itself. While the overall systemic toxicity of iodine is low, fatalities have occurred after accidental ingestion of iodine solutions. However, the pathological changes recorded for fatal cases of iodine poisoning are largely the result of tissue hypoxia and local corrosive destructive effects, rather than systemic iodine poisoning.
Another limitation for the germicidal use of iodine is its high aqueous insolubility (0.034% at 25.degree. C.). While the aqueous solubility of iodine may be increased through the use of alcohol (as for example, tincture of iodine) or through the use of inorganic metallic salts as solubilizing agents (as for example, sodium iodide and/or potassium iodide in the preparation of Lugols' Solution), such iodine solutions also possess the same toxic tissue manifestation which generally limit the use of iodine germicidal solutions.
When alcohol is used as a solvent for iodine, the use of such preparations on abraded and injured skin or mucous membrane is painful and damaging. Further, as the alcohol evaporates, the iodine content concentrates which increases the incidence of burning, corrosive destruction, and staining of tissues.
Metallic iodides have been used to solubilize elemental iodine in water through the direct formation of a water-soluble iodine complex formed between the diatomic iodine (I.sub.2) and the iodide ion (I.sup.-) to form I.sub.3.sup.- ions Such aqueous iodine solutions have not modified the toxic tissue reactions of elemental iodine, so that burning and staining still occur. In fact, such undesirable reactions are now more frequent, since larger concentrations of elemental iodine are utilized to prepare the aqueous iodine germicidal compositions.
Iodine in aqueous solution dissociates to equilibrium as follows: ##STR1## with the equilbrium constant (K.sub.1) being about 4.times.10.sup.-46 depending upon the temperature. In aqueous media, the dissociation phenomena for diatomic iodine is further complicated by the formation of several species of iodide ion, the most significant of which is the tri-iodide ion. The equilibrium constant (K.sub.2) is approximately 7.5.times.10.sup.2 for the following reaction: ##STR2## It is preferable to combine these equilibrium reactions when describing the dissociation of diatomic iodine in aqueous solutions as: ##STR3## the equilibrium constant (K.sub.3) being approximately 3.times.10.sup.-43.
Iodine is a mild oxidizing agent in acidic solution, with a redox equilibrium potential of 0.534 V at 25.degree. C. for the iodine-iodide ion couple. Iodine will readily oxidize sulfite to sulfate, and thiosulfate to tetrathionate, while ferric and cupric salts are reduced in acidic solution by the iodide ion, to form free iodine. In dilute solutions, iodine completely oxidizes sulfur dioxide to sulfuric acid, whereas iodides reduce sulfuric acid to sulfur dioxide, sulfur and even hydrogen sulfide, with the liberation of free iodine. In neutral or slightly alkaline aqueous solutions, iodine exerts a somewhat stronger oxidizing action because of the formation of hypo-iodite ion, in accordance with the following reaction: EQU I.sub.2 +2OH.sup.-.fwdarw.I.sup.- +IO.sup.- +H.sub.2 O
Such aqueous solutions are strong iodinating agents, and cause redox changes in body proteins and other biological substances within the alkaline physiologic pH range. Iodine will add to unsaturated linkages in tissue proteins, to cause denaturation which interrupt essential physiological reactions.
In an effort to overcome the noxious tissue toxicity observed for aqueous and hydroalcoholic solutions of iodine, while at the same time maintaining the germicidal and microbicidal activity of elemental iodine, water-soluble organic complexes of iodine with organic polymers were prepared. Combinations of elemental iodine and certain organic polymers, as for example polyvinylpyrrolidone and detergent polymers, has been shown to increase the aqueous solubility of elemental iodine. Such polymer-iodine complexes were termed iodophors.
The organic polymers used to form an iodophor comprise a broad range in molecular weight and chain length, and may be either ionic or nonionic in character, as well as possessing either surfactant or non-surfactant properties. A loose bond forms between the iodine and organic polymer to form the complex or iodophor, and aqueous solutions of up to 30% by weight in iodine content may be prepared (all percents are by weight herein, except as otherwise noted).
The general class of organic iodophor compounds comprises two distinct polymer groups: Polyvinylpyrrolidone, a non-detergent, non-ionic and non-surface active polymer; and a broad variety of detergent/surface-active polymers, including non-ionic, anionic, and cationic surface-active polymers. Both polymer groups are complexed with elemental iodine to form the iodophor. Anionic surface-active agents are generally not capable of providing stable iodine complexes. However, certain anionic surface-active agents, such as enumerated in U.S. Pat. No. 3,039,916, have been found to be suitable for forming iodine complexes for germicidal use.
Non-detergent, non-ionic organic polymers have generally not been employed as a carrier for iodine in germicidal use. Only one such polymer, polyvinylpyrrolidone, has to date been found satisfactory to complex with iodine to form useful iodophor germicidal compositions. Polyvinylpyrrolidone is a non-ionic, non-detergent, water-soluble synthetic organic polymer characterized by its unusual complexing ability and colloidal properties together with physiological inertness. The commonly employed, polyvinylpyrrolidone-iodine (PVP-I) complex contains from about 9 to 12% of titratable iodine, although polymer iodine complexes with both greater and lesser amounts of iodine are known. Polyvinylpyrrolidone iodine is a highly-effective germicide, providing a broad spectrum of microbicidal action against virtually all microbes.
Polyvinylpyrrolidone-iodine (PVP-I) exhibits low systemic toxicity, and is essentially non-irritating to mammalian tissue, in addition t being non-sensitizing and not causing pain when applied to wounds or mucous membrane.
Thus polyvinylpyrrolidone iodone (PVP-I) is extensively used as in important germicidal agent in man and animals, as well as in environmental uses. Polyvinylpyrrolidone iodine and the preparation thereof is described in U.S. Pat. No. 2,739,922. However, no other member of the non-detergent, non-ionic class of organic polymers has been found to be suitable for such antiseptic purposes.
The general method of preparing an iodophor complex is to bring the elemental diatomic iodine into intimate contact with the selected polymer either in the dry or powder form, or in the presence of a suitable solvent. Heat may be used to accelerate formation of the complex. Upon completion of the reaction, the iodophor complex of the respective polymeric carrier with iodine is obtained in certain reproducible proportions of one to the other.
Studies have demonstrated that the microbicidal potency of iodophor germicidal preparations is essentially the same as that known for aqueous and/or alcoholic solutions of elemental iodine, despite the modified tissue toxicity of the iodophors. Superiority of iodophor germicidal preparations over the aqueous and/or alcoholic inorganic elemental iodine solutions have been demonstrated to reside essentially in decreased toxicity, reduced tissue irritation, lowered iodine vapor pressure, as well as in the non-staining feature of skin and natural fabrics of the iodophor preparations.
Iodophor preparations are described in terms of available or titratable iodine which is considered to be the iodine released from the complex to exert its germicidal activity. However, such available iodine determinations do not either reflect the total iodine content of the iodophor or its germicidal potency.
As noted above, the most suitable polymer for the formation of iodophors is polyvinylpyrrolidone, which is the only nondetergent, nonionic organic polymer suitable for the formation of antiseptic iodophors.